A major cause of blindness in older adults is age-related macular degeneration (AMD). Its hallmarks are neovascularization and/or atrophy of photoreceptors and retinal pigment epithelial cells (RPE). The retina shows numerous changes prior to the development of atrophy, and at that stage individuals are considered to have age-related maculopathy (ARM). The long-term goal of this research is to accurately predict which individuals are at greatest risk for developing AMD. Our immediate goals are to use advanced biophysical techniques to test the hypothesis that high lipofuscin (accumulation of by-products of phagocytosis in RPE cells) is either a marker, or the cause, of advancing cell death. Specifically we will: (1) Test the hypothesis that the combined measurements of lipofuscin and Bruch's membrane deposits provide information that can ultimately be used to identify ARM patients at risk for more severe disease. To achieve this, we will compare the amounts of lipofuscin and Bruch's membrane deposits in older subjects with normal retinal status, subjects with bilateral ARM, and those with ARM in one eye and AMD (atrophy or neovascularization) in the other, and follow the patients to see if the those who have elevated levels of both lipofuscin and deposits progress to AMD. (2) Determine whether patients with ARM have significantly lower level of macular pigment and/or a different spatial distribution than age-matched normal controls. Since macular pigment is hypothesized to reduce oxidative damage to photoreceptors, determine whether there is a significant inverse relationship between macular pigment and RPE lipofuscin. (3) Examine evidence for genetic regulation of the accumulation of lipofuscin and/or macular pigment in monozygotic and dizygotic twins. (4) In longitudinal studies, determine whether the foci of elevated lipofuscin and/or its average level around borders of geographic atrophy correlate with rate or direction of greatest progression of subsequent atrophy, and whether discrete foci of hyperpigmentation consistently exhibit lipofuscin spectra. The proposed studies will provide needed data on relationships among AMD, lipofuscin and macular pigment, estimate genetic contribution to the latter, and assist identification of individuals at greatest risk for vision loss.